Semaglutide for MASH: What ESSENCE Trial Biopsy Results and FDA Accelerated Approval Show

Two records landed in August 2025. A peer-reviewed report in the New England Journal of Medicine detailed interim biopsy results from the ESSENCE trial of semaglutide in MASH. Days later, the FDA granted accelerated approval to Wegovy (semaglutide) for a narrow MASH indication. These developments matter. They also demand separation. Biopsy changes at 72 weeks signal histologic shifts. They do not prove reductions in cirrhosis progression, liver failure, transplants, or deaths.

What MASH Is, in Plain Language

MASH stands for metabolic dysfunction-associated steatohepatitis. It features excess fat buildup in the liver, paired with inflammation. Fibrosis often follows. Scarring builds silently. In advanced stages, it risks cirrhosis. The FDA estimates 6% of U.S. adults, or 14.9 million people, have MASH. Previously called NASH, the name shifted to reflect metabolic roots. No approved cures exist. Management focuses on root causes like obesity and type 2 diabetes.

What the ESSENCE Trial Measured

ESSENCE is an ongoing phase 3 trial, NCT04822181. Novo Nordisk funded it. Researchers enrolled 1197 adults with biopsy-confirmed MASH and fibrosis stages F2 or F3. No cirrhosis. Patients received once-weekly subcutaneous semaglutide 2.4 mg or placebo. Ratio: 2 to 1. Planned duration: 240 weeks.

This report covers part 1. An interim analysis at week 72 in the first 800 patients (534 semaglutide, 266 placebo). Primary endpoints: two-fold.

• Resolution of steatohepatitis without fibrosis worsening.
• Liver fibrosis reduction without steatohepatitis worsening.

What the 72-Week Results Show

Sanyal et al. reported in NEJM 2025. At week 72, in those 800 patients:

• Steatohepatitis resolution without fibrosis worsening: 62.9% with semaglutide vs 34.3% placebo. Difference: 28.7 points (95% CI 21.1-36.2; P<0.001).
• Fibrosis improvement without steatohepatitis worsening: 36.8% vs 22.4%. Difference: 14.4 points (95% CI 7.5-21.3; P<0.001).
• Both endpoints combined: 32.7% vs 16.1%. Difference: 16.5 points (95% CI 10.2-22.8; P<0.001).
• Mean body weight change: -10.5% vs -2.0%. Difference: -8.5 points (95% CI -9.6 to -7.4; P<0.001).

Gastrointestinal adverse events occurred more often with semaglutide.

What Accelerated Approval Means

On August 15, 2025, FDA approved Wegovy for adults with noncirrhotic MASH and F2-F3 fibrosis. Use: with reduced-calorie diet and increased activity. Basis: accelerated approval on biopsy surrogates from ESSENCE week 72. FDA cited similar figures: ~63% vs 34% resolution; ~37% vs 22% fibrosis improvement.

Label warns: continued approval may need confirmatory clinical benefit. Post-marketing requirement: complete NN9931-4553 trial by 2029. Endpoint: progression to cirrhosis, decompensation, transplant, mortality composite.

What Remains Unanswered

ESSENCE runs to 240 weeks. Clinical events data pending. Confirmatory trial required. Approval excludes cirrhosis (F4). Questions persist on durability off-drug, rare long-term harms, individual predictors.

How to Read These Numbers

Numbers reflect group averages in a trial population at 72 weeks versus placebo. A 62.9% rate means that share met the endpoint. Not a personal odds. Placebo groups improved too: 34.3% resolved inflammation; 22.4% cut fibrosis. Combined rates are lower. Weight loss accompanied changes. Sponsor: Novo Nordisk. GI events higher with drug.

Evidence-First Conclusion

Semaglutide MASH evidence from ESSENCE and FDA approval shows biopsy progress at 72 weeks in F2-F3 adults. Surrogates met. Clinical benefits await confirmation. This explainer separates records from regulators and journals. General education only. Not advice to seek, start, or skip treatment.

Source Trail

Peer-reviewed:

• Sanyal et al., NEJM 2025, PMID 40305708 | DOI

Registry:

• ClinicalTrials.gov NCT04822181

Regulatory (accessed August 22, 2026):

• FDA announcement
• FDA label S-024
• FDA approval letter
• Drugs@FDA overview